PATHOBIOLOGY OF NEURODEGENERATIVE DISEASES LINKED TO TAU GENE MUTATIONS

阿尔茨海默病(AD)和其他神经退行性疾病包括Pick病、进行性核上性瘫痪(PSP)、皮质基底膜变性(CBD)和一些额叶颞叶痴呆(FTD)的组织病理学特征是大脑神经元和神经胶质细胞中的包涵体。包涵体由微管相关蛋白tau组成。与正常脑中的tau不同的是，tau是一种可溶性蛋白质，能够促进微管蛋白的聚合形成微管，并稳定微管，而包裹体中的tau以丝状形式存在。形成Tau聚合物的机理(S)尚不清楚。最近的遗传学研究已经将tau突变与一些帕金森病(FTDP-17)引起的FTD联系在一起。已鉴定出几个错义突变(如G272V、N279K、P301L、V337M和R406W)和编码第二串联重复序列的外显子10的5个剪接点突变。后一种突变导致四对三重复tau的比率增加。目前尚不清楚是否存在突变型tau，或者是否存在足以使神经元和/或胶质细胞形成tau包涵体的4个和3个重复tau的异常比例。此外，目前还不清楚tau的功能是否受到这些突变的影响，不同的突变有不同的影响，或者这些突变是否改变了神经元退化的易感性。为了检测这些问题，重点研究FTDP-17中发现的突变体，(I)确定突变型和野生型tau在聚合潜能、对蛋白质分解的敏感性和其他物理化学特性方面是否存在差异，(Iii)研究培养细胞的反应以及项目3和4产生的转基因动物中tau基因的突变以及tau基因的突变，以及(V)研究转基因动物的神经元和胶质细胞培养，并确定携带突变型tau基因的小鼠的细胞对(A)微管稳定剂秋水仙碱，(B)磷酸酶抑制剂和(C)氧化应激的反应是否不同。

Alzheimer's disease (AD) and other neurodegenerative disorders including Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and some cases of frontal temporal dementia (FTD) are characterized histopathologically by inclusions in cerebral neurons and glia. The inclusions consists of microtubule associated protein, tau. In contrast to normal brain tau, which is a soluble protein capable of promoting the polymerization of tubu7lin to form microtubules (MT) and of stabilization of MT, tau in inclusions is in filamentous form. The mechanism(s) involved in formation of tau polymers remains to be elucidated. Recent genetic studies have linked tau mutations to a number of FTD with parkinsonism (FTDP-17) as the cause of taopathy. Several missence mutations (e.g. G272V, N279K, P301L, V337M and R406W) and mutations in the 5 splice site of exon 10, which encodes the second tandem repeat, have been identified. The latter mutations result in an increase of the ratio of four to three repeat tau. Whether the presence of mutant tau or the presence of an abnormal proportion of four and three repeat tau us sufficient for neuron and/or glia to form tau inclusion remains unclear at present. Moreover, it remains unclear if the function of tau is compromised by these mutations, iv various mutations have different effects, or if these mutations alter the susceptibility of neurons to degeneration. To examine these issues focusing on mutants identified in FTDP-17, (ii0 determine if mutant and wild type tau differ in polymerization potential, susceptibility to proteolysis and other physico-chemical properties, (iii) study the response of cultured cells and mutation in tau gene as well as tau in transgenic animals generated by Projects 3 and 4, and (v) study neuronal and glial cultures of transgenic animals and determine if cells from mice with mutant tau differ from those will wild type tau in response to (a) microtubule destabilizing agent colchicine, (b) phosphatase inhibitors, and (c) oxidant stress.